Advances in Diagnosis, Neurobiology, and Treatment of Mood Disorders June 13 - 14, 2016 Field House Coral Gables University of Miami Coral Gables, FL

The Epidemiology, Differential Diagnosis, and Course of Mood Disorders

Charles B. Nemeroff, M.D., PhD. Leonard M. Miller Professor and Chairman Department of Psychiatry and Behavioral Sciences Director, Center on Aging University of Miami, Miller School of Medicine Miami, Florida

Charles B. Nemeroff, MD, PhD Disclosures

●  Research/Grants: National Institutes of Health (NIH) ●  Consultant: Bracket (Clintara); Fortress Biotech; Gerson Lehrman Group, Inc.

●  ●  ●  ● 

(GLG) Healthcare & Biomedical Council; Lundbeck; Mitsubishi Tanabe Pharma Development America; Prismic Pharmaceuticals, Inc.; Sunovion Pharmaceuticals Inc.; Taisho Pharmaceutical Inc.; Takeda Pharmaceuticals North America, Inc.; Total Pain Solutions (TPS); Xhale, Inc.. StockholderAbbVie Inc.; Bracket; Celgene Corporation; Intermediate Holding Corp.; Network Life Sciences Inc.; OPKO Health, Inc.; Seattle Genetics, Inc.; Titan Pharmaceuticals, Inc.; Xhale, Inc. Income Sources or Equity of $10,000 or More: American Psychiatric Publishing; Bracket (Clintara); CME Outfitters, LLC; Takeda Pharmaceuticals North America, Inc.; Xhale, Inc. Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1) Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2) Scientific Advisory Board: American Foundation for Suicide Prevention (AFSP); Anxiety Disorders Association of America (ADAA); Bracket (Clintara); Brain & Behavior Research Foundation (BBRF) (formerly National Alliance for Research on Schizophrenia and Depression [NARSAD]); Laureate Institute for Brain Research, Inc. RiverMend Health, LLC; Skyland Trail; Xhale, Inc.

●  Board of Directors: American Foundation for Suicide Prevention (AFSP); Anxiety Disorders Association of America (ADAA); GratitudeAmerica, Inc.

Audience Response What percentage of patients with major depression are explicitly recognized as being depressed? A.  B.  C.  D. 

Less than 25% Between 30% - 40% Less than 50% Between 55% - 60%

Audience Response Which of the following pairs lists common observer-scored depression rating scales used in mental health? A.  Hamilton Scale of Depression and Montgomery-Åsberg Depression Rating Scale B.  Zung Depression Scale and Patient Health Questionnaire-9 C.  Minnesota Multiphasic Personality Inventory and Conners’ Rating Scale D.  Goldberg Depression and Mania Scales and Major Depression Inventory

Learning Objectives

● Define the role of epidemiology and differential diagnosis on the clinical course of mood disorders.

● Translate the latest evidence on the

importance of treating patients with mood disorders to remission.

● Implement measurement based care into the clinical management of patients with mood disorders.

All his life he suffered spells of depression, sinking into the brooding depths of melancholia, an emotional state which, though little understood, resembles the passing sadness of the normal man as a malignancy resembles a canker sore. William Manchester, The Last Lion, Winston Spencer Churchill, Vol. I: Visions of Glory (New York: Little, Brown & Company, 1989, p. 23)

Canst thou not minister to a mind diseased? Pluck from the memory a rooted sorrow, Raze out the written troubles of the brain, And with some sweet oblivious antidote Cleanse the stuffed bosom of that perilous Stuff which weighs upon the heart?

MACBETH

Major Depressive Disorder: DSM-5 Diagnostic Criteria A.  Five (or more) of the following symptoms have been present during the same 2-week

period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure: Note: Do not include symptoms that are clearly attributable to another medical condition.

1.  Depressed mood most of the day, nearly every day, as indicated by either subjective 2.  3.  4.  5.  6.  7.  8.  9. 

report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) Insomnia or hypersomnia nearly every day. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). Fatigue or loss of energy nearly every day. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. 2013. .

Major Depressive Disorder: DSM-5 Diagnostic Criteria B.  The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C.  The episode is not attributable to the physiological effects of a substance or to another medical condition.

Note: Criteria A-C represent a major depressive episode. Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the person's past history of major depressive episodes, whether the symptoms are disproportionately severe given the nature of the loss, and the individual's cultural norms for the expression of distress in the context of loss.

D.  The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

E.  There has never been a manic episode or a hypomanic episode. Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are substance-induced or are attributable to the physiological effects of another medical condition. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. 2013.

Major Depressive Disorder: DSM-5 Diagnostic Criteria Severity/course specifier  

Mild

 

Moderate Severe

 

Single episode  

  296.22 (F32.1)   296.23 (F32.2)   296.24 (F32.3)   296.25 (F32.4)   296.26 (F32.5)   296.20 (F32.9)   296.21 (F32.0)

   

With psychotic features In partial remission In full remission

 

Unspecified

 

 

Recurrent episode*  

  296.32 (F33.1)   296.33 (F33.2)   296.34 (F33.3)   296.35 (F33.4)   296.36 (F33.5)   296.30 (F33.9)   296.31 (F33.0)

*For an episode to be considered recurrent there must be an interval of at least 2 consecutive months between separate episodes in which criteria are not met for a major depressive episode. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. 2013. .

Major Depressive Disorder: DSM-5 Diagnostic Criteria Specify: If the full criteria are currently met for a major depressive episode, specify its current clinical status and/or features: With anxious distress With mixed features With melancholic features With atypical features 1In

distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief the predominant affect is feelings of emptiness and loss, while in MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhappiness and misery characteristic of MDE. The thought content associated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than tl1e self-critical or pessimistic ruminations seen in MOE. In grief, self-esteem is generally preserved, whereas in MOE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present in grief, it typically involves perceived failings vis à vis the deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying, such thoughts are generally focused on the deceased and possibly about "joining" the deceased, whereas in MDE such thoughts are focused on ending one's own life because of feeling worthless, undeserving of life, or unable to cope with tl1e pain of depression.

With mood-congruent psychotic features With mood-incongruent psychotic features With catatonic features Coding note: Use additional code 781.99 (R29.818). With peripartum onset With seasonal pattern (recurrent episode only)

Specify current or most recent episode: Single episode. Recurrent episode:Defined as the presence of two or more lifetime major depressive episodes. To be considered separate episodes, there must be an interval of at least 2 consecutive months in which criteria are not met for a major depressive episode. Specify current severity: Mild Moderate Severe Specify: Level of concern for suicide in the current assessment period regardless of current episode or remission status

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. 2013.

Major Changes in DSM-5

● Bereavement ● Elimination of chronic depression ● Severity/course specifier

Global Burden of Disease and Injury Series

THE GLOBAL BURDEN OF DISEASE A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020 EDITED BY CHRISTOPHER J. L. MURRAY Harvard University Boston, MA, USA ALAN D. LOPEZ World Health Organization Geneva, Switzerland

Published by The Harvard School of Public Health on behalf of The World Health Organization and The World Bank Distributed by Harvard University Press

Depression—A Major Cause of Disability Worldwide DALYs—2000 and 2020 Rank 20001 1 Lower respiratory infections 2 Perinatal conditions 3 HIV/AIDS 4 Unipolar major depression 5 Diarrheal diseases

2020 (Estimated)2 Ischemic heart disease Unipolar major depression Road traffic accidents Cerebrovascular disease COPD

DALYs = disability-adjusted life-years. COPD = chronic obstructive pulmonary disease 1.World Health Report 2001. Mental Health: New Understanding, New Hope. Geneva, World Health Organization, 2001. 2. Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston: Harvard University Press; 1996.

Mania Depression

Total mood variation

The Mood-Disorders Spectrum

Normals

Cyclothymia

Bipolar I Disorder

Bipolar II Disorder

Unipolar Depression

Dysthymia

Depression is Often Under Diagnosed and Inadequately Treated

● Less than 1/2 of patients with major

depression are explicitly recognized as being depressed1 ● Only about 1/2 of all depressed patients receive some form of therapy for their illness2 ● Only about 1/4 of depressed patients receive an adequate dose and duration of antidepressant treatment3 1. AHCPR. Rockville, Md: US Dept of Health and Human Services; 1993. Publication 93-0550. 2. Lepine JP, et al. Int Clin Psychopharmacol. 1997;12(1):19-29. 3. Katon W, et al. Med Care. 1992;30(1):67-76.

UP:BP 8% At Clinic Entry

Bipolar Unipolar

43% Bipolar

At 30-Yr Follow-up Unipolar Angst J, Sellaro R. Biol Psychiatry. 2000;48:445-457.

Symptom Domains of Bipolar Disorder Manic Mood and Behavior

•  •  •  •  •  •  •  • 

Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Social intrusiveness Diminished need for sleep

Dysphoric or Negative Mood and Behavior

Bipolar Disorder

•  •  •  •  • 

Cognitive Symptoms

Psychotic Symptoms

•  • 

Delusions Hallucinations

Depression Anxiety Irritability Hostility Violence or suicide

•  •  •  • 

Racing thoughts Distractibility Disorganization Inattentiveness

Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990:85-125.

History of Bipolar Disorder ●  1904: Kraepelin described symptoms recognized today as bipolar I disorder ●  1949: Discovery by Cade of lithium’s antimanic effects ●  1950s: Mogens Schou demonstrated short-term and prophylactic efficacy in bipolar I disorder ●  1962: Bipolar terminology introduced ●  1970s: Lithium given FDA approval for acute mania and maintenance therapy ●  1980: Bipolar disorder added to DSM ●  1980s: The anticonvulsants valproic acid and carbamazepine studied in bipolar disorder ●  1995: Divalproex given FDA approval for acute mania ●  2000: Olanzepine given FDA approval for acute mania ●  Present: Use of a variety of anticonvulsants and atypical antipsychotics in the treatment of bipolar disorder Adapted from Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 1994.

Epidemiology of Bipolar Disorder ●  Epidemiological Catchment Study1 lifetime prevalence: 1.2% (3.3 million people in US) ●  National Comorbidity Study2 lifetime prevalence: 1.6% (4 million people in US) ●  Surgeon General’s Report3 lifetime prevalence: 1.7%

●  Equal gender distribution1 1. Goodwin FK, Jamison KR, 1990. 2. Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19. PMID: 8279933 3. Office of the Surgeon General. Mental Health: A Report of the Surgeon General. 1999:228.

Course of Bipolar Illness ● Peak age of onset: 15 to 24 years1 ● High recurrence rate: >90% of patients

who have a single manic episode will have future episodes1 ● 10% to 15% of patients will have >10 episodes during their lifetime1,2 ● Course may vary with clinical subtype of bipolar disorder3 1.  2.  3. 

American Psychiatric Association. Am J Psychiatry. 1994;151(suppl 12):1-136. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990. Müeller-Oerlinghausen B, et al. Lancet. 2002;359:251-247.

Facts and Figures…

● The number of suicides in the United States in 2013 was 41,149.

● It exceeds the rate of homicide greatly. ● Suicide is the 10th leading cause of death in the United States.

● Of the 50 states, Florida is # 17 in suicide rate

Age-Adjusted Rate

Facts and Figures…

Suicide Rate (per 100,000)

Facts and Figures…

Crude Rate

Facts and Figures…

Suicide Deaths and Major Psychiatric Syndromes < 10% without Major Psychiatric Syndromes

> 90% with Major Psychiatric Syndromes

A number of psychological autopsy studies have found that approximately 90% of all completed suicides could be retrospectively diagnosed with a major mental disorder.

Suicide is an Outcomes that Requires Several Things to go Wrong All at Once There is No One Cause of Suicide and No Single Type of Suicidal Person Biological Factors

Predisposing Factors

Proximal Factors

Immediate Triggers

Familial Risk

Major Psychiatric Syndromes

Hopelessness

Public Humiliation Shame

Serotonergic Function

Substance Use/Abuse

Intoxication

Access To Weapons

Neurochemical Regulators

Personality Profile

Impulsiveness Aggressiveness

Severe Defeat

Demographics

Abuse Syndromes

Negative Expectancy

Major Loss

Pathophysiology

Severe Medical/ Neurological Illness

Severe Chronic Pain

Worsening Prognosis

Triggering Events ●  Loss of social support (friends, family) ●  Loss of identity/meaning (job, career, financial, legal problems) ●  Loss of independence/autonomy, or function (major health problem) ●  Acute psychiatric symptoms (psychosis, depression, panic…) ●  Loss of hope/Sense of failure ●  Date of a significant past interpersonal loss: Anniversary reaction

Ernest Hemingway

Adapted from Jamison (1993:229) Copyright 1993 by Kay Redfield Jamison. Adapted by permission.

Comorbidity Lifetime comorbidity of mood and anxiety disorders Up to 65% of patients with Panic Disorder2

48% of patients with PTSD1

Post-Traumatic Stress Disorder

Panic Disorder

DEPRESSION Social Anxiety Disorder

Up to 70% of patients with Social Anxiety Disorder5

GAD

OCD 67% of patients with Obsessive–Compulsive Disorder4

42% of patients with Generalised Anxiety Disorder3

Kessler et al. Arch Gen Psychiatry 1995;52(12);1048-1060; DSM-IV-TR™ 2000; Brawman-Mintzer et al. Am J Psychiatry 1993.150(8):1216-1218. ;Rasmussen et al. J Clin Psychiatry 1992 ; Dunner, Depression and Anxiety 2001;13(2):57-71.

Commonly Used Depression Symptom Severity Scales in Treatment Research

● Beck Depression Inventory (self-report) ● Hamilton Rating Scale for Depression

(clinician-rated) ● Montgomery Asberg Depression Rating Scale (clinician-rated) ● Inventory of Depressive Symptoms (full and quick versions self-report and clinician-rated versions) Bradley RG, et al. Arch Gen Psychiatry 2008;65(2):190-200.

Montgomery-Asberg Depression Rating Scale (MADRS) Measures 10 symptoms 1.  Apparent sadness 2.  Reported sadness 3.  Inner tension 4.  Reduced sleep 5.  Reduced appetite 6.  Concentration difficulties 7.  Lassitude 8.  Inability to feel 9.  Pessimistic thoughts 10.  Suicidal thoughts Montgomery S, Asberg M. Br J Psychiatry. 1979;134:382–389. .

Measuring the Severity of Depression and Remission in Primary Care: Validation of the HAMD-7 Scale

Roger S. McIntyre, Jakub Z. Konarski, Deborah A. Mancini, Kari A. Fulton, Sagar V. Parikh, Sophie Grigoriadis, Larry A. Grupp, David Bakish, MarieJosee Filteau, Chris Gorman, Charles B. Nemeroff, Sidney H. Kennedy McIntyre RS, et al. CMAJ. 2005;173(11):1327-1334.

The 7-item Hamilton Depression Rating Scale 1. Depressed mood (sadness, the blues, weepiness) • Have you been feeling down or depressed this past week? • How often have you felt this way, and for how long?

2. Feelings of guilt (self-criticism, self-reproach) • In the past week, have you felt guilty about something you’ve done, or that you’ve let others down? • Do you feel you’re being punished by being sick?

3. Interest, pleasure, level of activities (work and activities of daily living) • Are you as productive at work and at home as usual? • Have you felt interested in doing things that usually interest you?

4. Tension, nervousness (psychological anxiety) • Have you been feeling more tense or nervous than usual this week? • Have you been worrying a lot?

[ ] Absent [ ] Indicated only on questioning [ ] Spontaneously reported verbally [ ] Communicates nonverbally (facial expression, posture, voice, tendency to weep) [ ] Patient reports virtually only these feeling states in spontaneous verbal and nonverbal communication [ ] Absent [ ] Self-reproach (letting people down) [ ] Ideas of guilt or rumination over past errors or sinful deeds [ ] Present illness seen as punishment; delusions of guilt [ ] Hears accusatory or denunciatory voices or experiences threatening visual hallucinations [ ] No difficulty [ ] Fatigue, weakness or thoughts of incapacity (related to activities, work or hobbies) [ ] Loss of interest in activities (directly reported or indirectly through listlessness, indecision and vacillation) [ ] Decrease in actual time spent in activities or in productivity [ ] Stopped working because of current illness [ [ [ [ [

] No difficulty ] Subjective tension and irritability ] Worrying about minor matters ] Apprehensive attitude apparent in face or speech ] Fears expressed without questioning

McIntyre RS, et al. CMAJ. 2005;173(11):1327-1334. PMID: 16301700.

The 7-item Hamilton Depression Rating Scale 5. Physical symptoms of anxiety (somatic anxiety) • How much have these things been bothering you in this past week? DON’T RATE IF SYMPTOMS ARE CLEARLY DUE TO MEDICATION: • In the past week, have you had any of these symptoms? — Gastrointestinal: dry mouth, gas, indigestion, diarrhea, cramps, belching — Cardiovascular: heart palpitations, headaches — Respiratory: hyperventilation, sighing — Having to urinate frequently — Sweating

6. Energy level (somatic symptoms) • How has your energy been this past week? • Have you felt tired? • Have you had any aches or pains or felt any heaviness in your limbs, back or head?

7. Suicide (ideation, thoughts, plans, attempts) • Have you any thoughts life is not worth living or you'd be better off dead? • Have you thoughts of hurting or killing yourself? • Have you done anything to hurt yourself?

[ [ [ [ [

] Absent ] Mild ] Moderate ] Severe ] Incapacitating

[ ] None [ ] Heaviness in limbs, back or head (backache, headache, muscle aches; loss of energy and fatigability) [ ] Any clear-cut symptom rates 2 points [ ] Absent [ ] Feels life is not worth living [ ] Wishes to be dead (or any thoughts of possible death to self) [ ] Suicidal ideas or gestures [ ] Attempts at suicide (any serious attempt rates 4)

Total score:

McIntyre RS, et al. CMAJ. 2005;173(11):1327-1334. PMID: 16301700.

Background: Symptomatic remission is the optimal outcome in depression. A brief, validated tool for symptom measurement that can indicate when remission has occurred in mental health and primary care settings is unavailable. We evaluated a 7-item abbreviated version (HAMD-7) of the 17-item Hamilton Depression Rating Scale (HAMD-17) in a randomized controlled clinical trial of patients with major depressive disorder being cared for in primary care settings. Methods: We enrolled 454 patients across 47 primary care settings who met DSMIV-TR criteria for a major depressive disorder. Of these, 410 patients requiring antidepressant medication were randomized to have their symptoms rated with either HAMD-7 ( n= 205) or HAMD-17 ( n= 205) as the primary measurement tool. The primary outcome was the proportion of patients who achieved a-priori defined responses to 8 weeks of therapy using each instrument. Results: Of the 205 participants per group, 67% of those evaluated with HAMD-7 were classified as having responded to therapy (defined as a 50% reduction from the pretreatment score), compared with 74% of those evaluated with HAMD-17 ( p= 0.43). The difference between the groups’ changes in scores from baseline (pretreatment) to endpoint was significant ( p< 0.001), without a main effect of group ( p= 0.84) or groupby-time ( p= 0.83) interaction. The HAMD-7 test was brief to administer (e.g., 3–4 min for 85% of the primary care physicians evaluated), which facilitated the efficient and structured evaluation of salient depressive symptoms. Interpretation: The abbreviated HAMD-7 depression scale is equivalent to the HAMD-17 in assessing remission in patients with a major depressive disorder undergoing drug therapy. McIntyre RS, et al. CMAJ. 2005;173(11):1327-1334. PMID: 16301700.

Outcomes of Treatment Outcome

Commonly Accepted Definition

Response

Clinical significant reduction in baseline symptom severity

Remission

Absence of symptoms

Recovery

Sustained period of remission following an episode of major depression

Relapse

Return of a major depressive episode during continuation treatment (ie, before recovery)

New episode of depressive following Recurrence recovery of previous episode Depression Guideline Panel; 1993. AHCPR publication 93-0550. Frank E, et al. Arch Gen Psychiatry. 1991;48(9):851-855.

Remission

● Minimal or no symptoms

● No longer meets diagnostic criteria ● Sustained remission: return to “functional normality” ● Remission for ≥8 wk usually associated with

restoration of daily functioning ● Typically, cannot be distinguished from those without depression

DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. Thase ME, et al. Br J Psychiatry. 2001;178:234-241. Frank E, et al. Arch Gen Psychiatry. 1991;48(9):851-855. Rush AJ, et al. Psychiatr Ann. 1995;25:704.

Operational Definition of Remission Remission = HAM-D17 ≤ 7

0 Minimal or no 7 symptoms

15 Fully symptomatic

30

Severe depression

Hamilton depression rating scale (HAM-D17)

Frank E, et al. Arch Gen Psychiatry. 1991;48:851-855.; Rush AJ, et al. Psychiatr Ann. 1995;25:704. American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Major Depression. 2nd ed. 2000; Anderson IM, et al. J Psychopharmacol. 2000;14:3-20.

Outcome of Depression Treatment: The Five Rs

Reproduced with permission from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. Copyright 2002, Physicians Postgraduate Press.

Potential Consequences of Failing to Achieve Remission ●  Increased risk of relapse and treatment resistance ●  Continued psychosocial limitations ●  Decreased ability to work and decreased workplace productivity ●  Increased cost for medical treatment ●  Sustained risk of suicide, substance abuse ●  Sustained depression can worsen morbidity/ mortality of other conditions

Paykel ES, et al. Psychol Med. 1995;25(6):1171-1180.; Thase ME, et al. Am J Psychiatry. 1992;149:1046-1052. Judd LL, et al. J Affect Disord. 1998;59:97-108.; Miller IW, et al. J Clin Psychiatry. 1998;59:608-619.; Simon GE, et al. Gen Hosp Psychiatry. 2000;22(3):153-162.; Druss BG, et al. Am J Psychiatry. 2001;158(5):731-734.; Frasure-Smith N, et al. JAMA. 1993;270(15):1819-1825.; Penninx BW, et al. Arch Gen Psychiatry. 2001;58(3):221-227. Rovner BW, et al. JAMA. 1991;265:993-996.

Achieving Remission Decreases Risk of Relapse

Thase ME, et al. Am J Psychiatry. 1992;149:1046-1052.

Depression Worsens Outcomes of Many General Medical Conditions ●  Depression worsens morbidity and mortality

after myocardial infarction1,2 ●  Depression increases risk for mortality in patients in nursing homes3 ●  Depression worsens morbidity post-stroke4 ●  Depression can worsen outcomes of cancer, diabetes, AIDS, and other disorders5 1.Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.; 2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227.; 3. Rovner BW, et al. JAMA. 1991;265:993-996.; 4. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319. 5. Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84.

Depression Increases Risk of Cardiac Mortality

RR cardiac mortality (and 95% CI)

5 4

Nondepressed Minor depression Major depression

3 2 1 0

No pre-existing cardiac disease

Pre-existing cardiac disease

Penninx BW, et al. Arch Gen Psychiatry. 2001;58(3):221-227.

Risk Factors for Delayed Remission

● Chronicity

● Longer length of episode ● Number of previous episodes ● Medical comorbidity ● Older age ● Axis I or II comorbidity ● Severity Thase ME, et al. Am J Psychiatry. 1997;58(suppl 13):23-29. Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11. Thase ME. J Clin Psychiatry. 1999;60(suppl 22):3-6.

Potential Obstacles to Attaining Remission in Clinical Practice

● Patients and clinicians are satisfied with partial improvement in symptoms (ie, response but not remission) ● Treatments may not be well tolerated

● Underdosing ● Failure to recognize residual symptoms Keller MB, et al. Arch Gen Psychiatry. 1992;49(10):809-816.

Increasing the Likelihood of Remission

● Measure outcomes! ● Optimize dose/extend trial ● Selection of antidepressant ● Role of adherence ● Pharmacologic adjuncts ● Role of psychotherapy Rush AJ, et al. J Clin Psychiatry. 1997;58(suppl 13):14-22. Thase ME, et al. Am J Psychiatry. 1999;60(suppl 22):3-6.

Age at First Onset of Major Depression

Weissman MM.et al. JAMA. 1996;276(4):293.

Leading Causes of Disease Burden for Women in the United States

MDD = major depressive disorder; COPD = chronic obstructive pulmonary disease; DALY = disabilityadjusted life-year. *Also includes other degenerative and hereditary CNS disorders. Michaud CM, et al. JAMA. 2001;285(5):535-539. PMID: 11176854.

Gender Differences in Comorbidities with Depression More Common in Men ●  Alcohol abuse/ dependence1 ●  Substance abuse/ dependence1 ●  Stimulant ●  Cannabis ●  Cocaine ●  Hallucinogen

1Kornstein

S et al. Presented at American Psychiatric Association; May 4-9, 1996; New York, NY.

2Fava M, et al. J Affect Disord. 1996;38(2-3):129-133. 3Kornstein SG. J Clin Psychiatry. 2002;63:602-609. 4Moldin

More Common in Women ●  Panic disorder1 ●  GAD1 ●  Social phobia2 ●  Bulimia1,2 ●  Thyroid disease3 ●  Migraine headaches3,4 ●  Fibromyalgia3 ●  Chronic fatigue syndrome3

SO, et al. Psychol Med. 1993;23(3):755-761.

Mood and Anxiety Disorders Across the Female Reproductive Cycle

Postpartum Depression (PPD)

● 10% to 15% in adults* ● 26% of adolescents†

*Stowe Z., Nemeroff C. Am J Obstet Gynecol. 1995; 173(2): 639-645. †Troutman and Cutrona. J Abnorm Psychol. 1990; 99(1): 69.

Depressive Disorders After Miscarriage

● >33% severely depressed* ● ↑ duration of pregnancy = ↑ risk of

depressive disorder* ● Treat depressive disorders if reaction beyond expected grief and bereavement

*From Janssen JH, et al. Am J Psychiatry. 1996;153(2): 226-230.

PMDD: Background

● 75% of women report minor, isolated, or occasional premenstrual changes ● 20% – 50% report “premenstrual syndrome” ● 3% – 8% of reproductive-age women have PMDD PMDD = premenstrual dysphoric disorder. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fourth edition. 1994. Angst. Eur Neuropsychopharmacol. 1999;9:S144; Haskett. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11(2-3): 129-135.; Johnson SR, et al.J Reprod Med. 1988;33(4):340-346.; Ramcharan S, et al. J Clin Epidemiol. 1992;45(4): 377-392.; Rivera-Tovar AD, Frank E. Am J Psychiatry. 1990;147(12):1634-1636.

PMDD

Depression

Premenstrual Exacerbation (PME) ●  Prospective Monthly Charting for accurate Diagnosis ●  Worsening of symptoms during luteal phase of

menstrual cycle ●  Distinction from PMDD is presence of ongoing symptoms during follicular phase of cycle ●  Premenstrual exacerbation of symptoms may be seen with many disorders, including ●  Anxiety disorders ●  Eating disorders ●  Substance abuse ●  Seizures ●  Migraines ●  Asthma PMDD = premenstrual dysphoric disorder. Endicott J. J Affect Disord. 1993;29(2-3):193-200.

Depressive Disorders in Children Prevalence of Depressive Disorders in Children* ●  Preschool children – 0.8% ●  School-aged prepubertal children – 2.0% ●  Adolescents – 4.5% Key Issues† ●  Distinguish between depressive disorders and behavioral disorders ●  Depressive disorders before age 20 often associated with recurrent mood disorders in adulthood ●  30% of adolescents hospitalized with severe major depressive disorder develop bipolar disorder *Weller EB, Weller RA. In: Psychiatric Disorders in Children and Adolescents. 1990: 3-20. †Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65. Giles DE, Jarrett RB, Biggs MM, et al. Am J Psychiatry. 1989; 146: 765-767. Strober M, Carlson G. Arch Gen Psychiatry. 1982; 39(5): 549-555.

Depressive Disorders in Older Age

● Occur in approximately 15% of population >65 years old

● May mimic dementia ● Comorbid somatic symptoms ● Not due to “old age” ● Require appropriate treatment Data from NIH Consensus Development Panel on Depression in Late Life. JAMA. 1992; 288: 1018-1024.

Treatment Resistance and Depressive Sub-Types ● Atypical depression ● “Double” depression ● Psychotic depression ● Severe and melancholic depression ● Co-morbidity — psychiatric or medical ● Psychosocial stressors

21st Century Medicine

Risk Factors for Depressive Disorders ●  Family History of depressive disorders ●  Prior personal history of a depressive disorder ●  Female gender ●  Life stressor (eg, bereavement, chronic financial problems) ●  Certain personality traits ●  Loss of parents at an early age ●  Childhood abuse ●  Alcohol or drug abuse ●  Anxiety disorders ●  Neurologic disorders (eg, Parkinson’s, Alzheimer’s, stroke) ●  Primary sleep disorders Hirschfeld RMA, Goodwin FK. In: The American Psychiatric Press Textbook of Psychiatry. 1987: 403-441 Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65

Audience Response What percentage of patients with major depression are explicitly recognized as being depressed? A.  B.  C.  D. 

Less than 25% Between 30% - 40% Less than 50% Between 55% - 60%

Audience Response Which of the following pairs lists common observer-scored depression rating scales used in mental health? A.  Hamilton Scale of Depression and Montgomery-Åsberg Depression Rating Scale B.  Zung Depression Scale and Patient Health Questionnaire-9 C.  Minnesota Multiphasic Personality Inventory and Conners’ Rating Scale D.  Goldberg Depression and Mania Scales and Major Depression Inventory

Questions?